α1-Acid Glycoprotein Decreases Neutrophil Migration and Increases Susceptibility to Sepsis in Diabetic Mice

• Published in: Diabetes (New York, N.Y.) Vol. 61; no. 6; pp. 1584 - 1591
• Main Authors: SPILLER, Fernando, CARLOS, Daniela, SOUTO, Fabricio O, DE FREITAS, Andressa, SOARES, Fernanda S, VIEIRA, Silvio M, PAULA, Francisco J. A, ALVES-FILHO, Jose C, CUNHA, Fernando Q
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.06.2012
• Subjects: Animals; Biological and medical sciences; CD11b Antigen - metabolism; Cell Movement - drug effects; Cell Movement - immunology; Complications; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - immunology; Diabetes Mellitus, Experimental - metabolism; Diabetes. Impaired glucose tolerance; Diabetics; Disease Susceptibility - immunology; Disease Susceptibility - metabolism; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Glycoproteins; Health aspects; Insulin - pharmacology; Insulin - therapeutic use; L-Selectin - metabolism; Medical sciences; Mice; Neutrophil Infiltration - drug effects; Neutrophil Infiltration - immunology; Neutrophils; Neutrophils - drug effects; Neutrophils - immunology; Neutrophils - metabolism; Orosomucoid - metabolism; Physiological aspects; Risk factors; Sepsis; Sepsis - immunology; Sepsis - metabolism; Brazil; Endocrinopathy; Infection; Sepsis syndrome; Vertebrata; Sensitivity; Mammalia; Mouse; Animal; Diabetes mellitus; Rodentia; Glycoprotein; Neutrophil
• DOI: 10.2337/db11-0825
• ISSN: 0012-1797

The mechanisms underlying immune deficiency in diabetes are largely unknown. In the present study, we demonstrate that diabetic mice are highly susceptible to polymicrobial sepsis due to reduction in rolling, adhesion, and migration of leukocytes to the focus of infection. In addition, after sepsis induction, CXCR2 was strongly downregulated in neutrophils from diabetic mice compared with nondiabetic mice. Furthermore, CXCR2 downregulation was associated with increased G-protein-coupled receptor kinase 2 (GRK2) expression in these cells. Different from nondiabetic mice, diabetic animals submitted to mild sepsis displayed a significant augment in α1-acid glycoprotein (AGP) hepatic mRNA expression and serum protein levels. Administration of AGP in nondiabetic mice subjected to mild sepsis inhibited the neutrophil migration to the focus of infection, as well as induced l-selectin shedding and rise in CD11b of blood neutrophils. Insulin treatment of diabetic mice reduced mortality rate, prevented the failure of neutrophil migration, impaired GRK2-mediated CXCR2 downregulation, and decreased the generation of AGP. Finally, administration of AGP abolished the effect of insulin treatment in diabetic mice. Together, these data suggest that AGP may be involved in reduction of neutrophil migration and increased susceptibility to sepsis in diabetic mice.